Liver Abscesses and Granulomas: Bacteria can reach the liver via a number of different routes and form abscesses (Figs. 8-41 to 8-43). Routes include the following:

Both Gram-positive and Gram-negative organisms can cause hepatic abscesses. In adult small animals, hepatic abscesses are often caused by any of a variety of enteric species, as well as Francisella spp., Nocardia asteroides, and Actinomyces spp. Bacterial infections of the liver and subsequent formation of hepatic abscesses or foci of necrosis are especially common in neonatal foals and ruminants, in addition to feedlot cattle. In feedlot cattle, hepatic abscesses usually occur as a sequel to toxic rumenitis because damage to the ruminal mucosa allows ruminal microflora, particularly Fusobacterium necrophorum, to enter the portal circulation. After initially localizing within the liver, bacteria proliferate and produce focal areas of hepatocellular necrosis and hepatitis that can in time develop into hepatic abscesses (Fig. 8-44). Liver abscesses of cattle frequently are incidental lesions, but they can cause weight loss and decreased milk production. Less commonly, a hepatic abscess encroaches on the lumen of either a hepatic vein or the caudal vena cava. This can cause phlebitis that results in mural thrombosis, and because of the obstruction of the outflow to the venous drainage of the liver, passive congestion of the liver and portal hypertension can occur (Fig. 8-45). Detachment of portions of these mural thrombi can produce septic thromboemboli that lodge in the lungs. Rupture of hepatic abscesses directly into the hepatic vein or into the caudal vena cava occurs sporadically in cattle and may result in fatal septic embolization of the lungs. Sometimes death can be sudden from the blockage of large areas of pulmonary capillaries by the exudate. Hepatic abscesses derived from bacteria arriving via the portal vein may not be evenly distributed throughout the liver, possibly because of selective distribution of portal blood into different liver lobes, termed portal streaming. Occasionally, fungi, such as Mucor sp., that proliferate in areas of ruminal ulceration invade the portal circulation and are carried to the liver and there cause extensive areas of necrosis and inflammation (Fig. 8-46).

Tuberculosis (Mycobacterium bovis) has been eradicated from almost all of the United States (US), but its occurrence in other countries varies with the effectiveness of control efforts. The primary site of the disease is pulmonary with subsequent dissemination to other organs, including the liver. Other domestic animal species can be infected with Mycobacterium bovis, and it is also a zoonotic microbe. Mycobacterium avium-intracellulare complex can occur in domestic animals, especially dogs, in the southern areas of the US. Granulomas are randomly distributed (i.e., hematogenous spread) in the liver. They have a central core of cell debris, caseation, and granulomatous inflammation surrounded by a fibrous capsule (Fig. 8-47).

Tyzzer’s Disease: This disease is caused by Clostridium piliforme (formerly Bacillus piliformis), a Gram-negative obligate intracellular parasite. It is well recognized in laboratory animals but occurs only sporadically in domestic animals. Infection is most common in foals but has been described in calves, cats, and dogs and many other species. Typically, only very young or immunocompromised animals are affected. The bacteria are found in the intestinal tract of rodents. Infection is most likely through the oral route. The mechanisms of attachment and entry into host cells are unknown. After colonization of the gastrointestinal tract, organisms penetrate into the portal venous drainage and enter the liver. The disease is characterized by enlarged, edematous, and hemorrhagic abdominal lymph nodes, hepatic enlargement, and the presence of randomly distributed, pale foci of hepatocellular necrosis surrounded by a variably intense inflammatory infiltrate of neutrophils and mononuclear cells (Fig. 8-48, A). Diagnosis requires the demonstration of the characteristic, elongated large bacilli within viable hepatocytes at the margins of necrotic foci (Fig. 8-48, B). Silver stains, such as Warthin-Starry or Gomori’s silver stain, are frequently used for this purpose (Fig. 8-48, C).

Leptospirosis: Leptospirosis is caused by infection with the Gram-negative, thin, spiral, and motile bacterium of the genus Leptospira. There are two species, of which Leptospira interrogans is capable of causing disease in animals. The taxonomy of these organisms is complicated because there are more than 23 antigenically distinct pathogenic serogroups and 200 serovars. Each serovar can differ with respect to the species affected, organs affected, and severity of disease. Leptospires enter the body through the mucous membranes or through the skin if its barrier functions have been disrupted. Contaminated water, bedding, and soil are common sources of infection because the organism is shed in urine. Fetuses can develop transplacental infection and are often aborted. Infection can involve red blood cells, kidney, liver, and a number of other tissues, depending on the infecting serovar. The liver is often involved in acute, severe leptospirosis of all domestic species because a number of serovars cause intravascular hemolytic anemia leading to ischemic injury to centrilobular areas. Furthermore, organisms can be seen in large numbers in the liver after silver staining methods, although the direct effects of leptospira toxins on hepatocytes are less well established.

Gross lesions include icterus when animals are infected with serovars that produce hemolysis. Hepatic hemorrhage and ascites can occur, depending on the course of infection and the serovar involved. In some cases, acute infection can cause focal necrosis in addition to or instead of centrilobular necrosis. A common but nonspecific change in the liver of infected dogs is dissociation of hepatocytes. Affected cells become rounded and have eosinophilic granular cytoplasm and dark, shrunken hyperbasophilic nuclei. Bile casts in canaliculi are often apparent. Kupffer cells may contain abundant hemosiderin. Infection of dogs with Leptospira grippotyphosa has been reported to produce chronic (chronic-active) hepatitis, but it is unlikely that leptospira are involved in the pathogenesis of the majority of spontaneous cases of chronic hepatitis.

Other Bacterial Infections: These diseases are grouped together because they all arise from a bacteremia that occurs during a systemic infection. A comprehensive list of systemic infections that may produce hepatocellular necrosis and hepatitis is beyond the scope of this chapter, but examples include Yersinia pseudotuberculosis, Salmonella spp. (lesions present within the liver are discrete accumulations of mixed mononuclear inflammatory cells, which often are referred to as paratyphoid nodules) and Brucella spp. infection in many species (Fig. 8-49, A and B). Haemophilus agni and Pasteurella haemolytica can present as infections in sheep. Other infections include Arcanobacter pyogenes (Actinomyces pyogenes) of the bovine fetus and neonate, Campylobacter fetus ssp. fetus in fetal and neonatal lambs (Fig. 8-50), Actinobacillus equuli infection of neonatal foals, and Nocardia asteroides infection of dogs. Yersinia tularensis (Francisella tularensis), the cause of tularemia, can occur in cats and dogs. Bacterial infections such as these may produce lesions within the liver that range from small foci of hepatic necrosis to multiple, large abscesses. Determination of the specific causative agent often depends on bacterial isolation and characterization.

Bacillary hemoglobinuria and infectious necrotic hepatitis, both due to species of Clostridia, are described in detail in the section on Disorders of Ruminants.

Nematodes: Migration of larvae through the liver is a common component of a nematode’s life cycle in domestic animals. As larvae travel through the liver, they produce local tracts of hepatocellular necrosis that are accompanied by inflammation. These tracts are eventually replaced with connective tissue that matures into fibrous scars and which are especially prominent on the capsular surface (Fig. 8-52). These capsular scars appear as pale areas, and the term milk-spotted liver has been used to describe livers in pigs scarred by migrating larvae of Ascaris suum. Larvae occasionally become entrapped within the liver or its capsule and are walled off within abscesses or granulomas. Examples of chronic hepatitis or hepatic scarring as a consequence of larval migration include migration of ascarids in several species of domestic animals, such as Stephanurus dentatus in pigs, and Strongylus sp. in the horse. Infection of the liver with adult nematodes is considerably less common than larval migration. Calodium hepatica occasionally may be found in the hepatic parenchyma of dogs and cats where the ova provoke granulomatous inflammation.

Dogs with heartworm infection (Dirofilaria immitis) occasionally develop vena caval syndrome, also known as the postcaval syndrome, which is characterized by DIC, intravascular hemolysis, and acute hepatic failure. The syndrome typically occurs in dogs with large numbers of adult worms in the vena cava and their more usual location within the right side of the heart and pulmonary artery (Fig. 8-53). The liver is engorged with blood as a consequence of severe passive congestion from the partial blockage of the caudal vena cava. It is proposed that mechanical factors produced by the presence of large numbers of worms in the right atrium or caudal vena cava are the cause of intravascular hemolysis, which characterizes vena caval syndrome, although other theories suggest that there may be a hypersensitivity reaction to antigens released by the worms.

Cestodes: A number of cestodes occur within the hepatobiliary system of domestic animals. Those cestode parasites of greatest clinical significance develop encysted forms within the liver of the intermediate hosts. The most important are larval cestodes of the genus Taenia; adults inhabit the gastrointestinal tract of carnivores and usually are innocuous to their definitive host. The ova ingested by an intermediate host develop into embryos, which penetrate the wall of the gut and then are distributed via the blood to virtually any site in the body. Parasitic cysts develop within the tissue of the intermediate host, and the life cycle of the parasite is completed when the cysts are ingested by the definitive host. Although the liver is but one organ in the intermediate host that may be affected, hepatic involvement is common because portal blood, in which embryos migrate, drains into the liver before flowing to the systemic circulation.

The adult cestode Taenia hydatigena shows up in the small intestine of dogs, whereas its intermediate stage, Cysticercus tenuicollis, appears in the peritoneal cavity of a variety of species, including horses, ruminants, and pigs (Fig. 8-54). Immature cysticerci migrate in the liver and can induce extensive damage if infection is heavy; lesions present are comparable to those induced by migration of immature Fasciola hepatica.

Hydatid liver disease is common in some countries. Echinococcus granulosus is a cestode that parasitizes canids as the definitive host, and hydatid cysts can develop in many different intermediate host animal species, including humans. The dog-sheep cycle is most important in many geographic areas. Pastured cattle are also commonly affected in other geographic locations. Adult worms in the intestines of dogs pass proglottids into the dog’s stool and thereby contaminate pastures. Ova are then ingested by sheep, cattle, or other species. Embryos may develop into hydatid cysts in virtually any organ in the intermediate host, but the liver and lungs are commonly affected. These cysts are usually less than 10 cm in diameter but can attain quite a spectacular size, particularly in humans. Hydatid cysts, even when present in large numbers, rarely cause overt clinical signs of disease in domestic animals.

Cestode adults occurring within the hepatobiliary system include Stilesia hepatica, Stilesia globipunctata, and Thysanosoma actinoides, all of which can inhabit the bile duct of ruminants. Infections with these parasites may result in chronic inflammation of the biliary tract, but they usually do not produce clinical signs of hepatic dysfunction.

Trematodes: The majority of parasitic hepatic injury caused by trematodes is produced by members of three major families. These include the families Fasciolidae, Dicrocoelidae, and Opisthorchidae.

The principal liver fluke disease of sheep and cattle and occasionally other species is caused by Fasciola hepatica. Hepatic fascioliasis occurs throughout the world in areas where climatic conditions, typically in low swampy areas, are suitable for the survival of aquatic snails, which serve as intermediate hosts for the parasites. Adult Fasciola hepatica are leaf-shaped parasites that inhabit the biliary system; their eggs pass via the bile to the intestinal tract and eventually are passed in the feces. Larvae (miracidium) then must develop in the snail intermediate host (genus Lymnaea). Cercariae that leave the snail encyst on herbage where they develop into infectious metacercariae. Metacercariae are ingested by the ruminant host and penetrate the wall of the duodenum to enter the peritoneal cavity and subsequently enter the liver. They migrate within the liver before taking up residence within the bile ducts. Migration of immature flukes through the liver produces hemorrhagic tracts of necrotic liver parenchyma. These tracts are grossly visible and in acute infection are dark red, but with time become paler than the surrounding parenchyma. Repair is often by fibrosis. A variety of untoward sequelae can follow these migrations, including acute peritonitis; hepatic abscesses; death of the host as a consequence of acute, widespread hepatic necrosis produced by a massive infiltration of immature flukes; and the proliferation of spores of Clostridium haemolyticum or Clostridium novyi in necrotic tissue, which causes the subsequent development of bacillary hemoglobinuria or infectious necrotic hepatitis, respectively.

Mature flukes reside in the larger extrahepatic and intrahepatic bile ducts and cause cholangitis. Chronic cholangitis and bile duct obstruction lead to ectasia and stenosis of the ducts and periductular fibrosis that thickens the walls so that the ducts become increasingly prominent. Mineralization may occur producing the classic “pipestem” appearance of diseased bile ducts. The contents of the bile ducts are often dark brown and viscous caused by a combination of abnormal bile, cellular debris, and the iron-porphyrin pigment excreted by the flukes. Obstruction of the ducts leads to cholestasis. Animals with chronic liver fluke disease are often in poor body condition.

Fasciola gigantica and Fascioloides magna are important causes of liver fluke disease of ruminants in some parts of the world. Fasciola gigantica is most common in areas of Africa and surrounding countries, and Fascioloides magna is found in North America. The adults of Fasciola gigantica and Fasciola hepatica reside in the bile ducts (Fig. 8-55). In contrast, adult Fascioloides magna, whose normal hosts are elk and white-tailed deer, reside in the hepatic parenchyma in aberrant hosts, such as cattle and sheep. In cattle, the immature Fascioloides magna flukes cause extensive tissue damage as they migrate through the liver (Fig. 8-56), but the adults are enclosed by fibrous connective tissue in cysts containing a black fluid. In sheep and goats, the flukes continuously migrate through the liver, causing extensive damage and eventual death.

Other trematodes that may inhabit the bile ducts include Dicrocoelium dendriticum in horses, ruminants, pigs, dogs, and cats; Eurytrema pancreaticum and Eurytrema coelomaticum in ruminants; Opisthorchis tenuicollis in pigs, dogs, and cats and Opisthorchis felineus in dogs and cats; Pseudamphistomum truncatum, Metorchis conjunctus, Metorchis albidus, Parametorchis complexus, Concinnum procyonis, and Platynosomum fastosum in dogs and cats. All are capable of inducing changes similar to but usually considerably milder than those caused by Fasciola hepatica. In addition, they occasionally cause obstruction of the biliary ducts.

Cats, and less often dogs, can develop pronounced chronic cholangitis from infections with flukes, most often Opisthorchiidae. Microscopically, larger intrahepatic bile ducts are dramatically thickened by concentric fibrosis and the duct lumen is usually dilated, often with papillary projections of biliary epithelium into the lumen (Fig. 8-57). A mild-to-moderate inflammatory infiltrate of neutrophils and macrophages is often found in and around the ducts, and the portal tracts are infiltrated by neutrophils, lymphocytes, and plasma cells. Eosinophils are generally uncommon. It is often difficult to detect adult flukes or ova in affected animals.

Dogs can be infected with the schistosome Heterobilharzia americana, which is normally a parasite in raccoons. Ova shed into water by infected raccoons release miracidia, which penetrate host snails. Dogs become infected when their skin is penetrated by cercariae, which are released from the intermediate snail hosts. Granulomatous lesions of the liver, pancreas, intestines, and mesentery result when ova released by adult schistosomes lodge in affected tissue and incite an inflammatory reaction.

Hepatotoxic Bacteria Blue-Green Algae: Blue-green algae are classified in the phylum Monera, division Cyanophyta; are considered to be more closely related to bacteria; and are no longer considered members of the plant family. Several genera of blue-green algae, including Anabaena, Aphanizomenon, and Microcystis, can cause lethal poisoning of livestock and less commonly small animals such as dogs and cats. Algal blooms usually occur in late summer or early fall because of the warm temperatures, long hours of sunlight, and abundance of essential nutrients. Dead and dying algae, which contain preformed toxins, such as microcystin LR, a cyclic heptapeptide, accumulate on the surface of bodies of water and are ingested by livestock. Secondary bacterial growth in dying algae may contribute to toxin formation. Signs develop rapidly and include diarrhea, prostration, and death. Gross lesions include hemorrhagic gastroenteritis and a red, swollen, hemorrhagic liver. Histologically, centrilobular, or even massive, hepatic necrosis and hemorrhage is evident. Animals that survive the acute manifestations may develop clinical signs of chronic liver disease. Other preformed toxins that affect different organ systems, including the nervous system, have also been identified in blue-green algae.

Hepatotoxic Plants: Toxic plants of great variety cause hepatic injury in domestic animals. A comprehensive discussion of each is beyond the scope of this chapter.

Mycotoxins: Mycotoxins are secondary metabolites of fungi, that is, their production is not necessary for the survival of the fungus. The amount of toxin synthesized by a given strain of fungus reflects the genetic constitution of the particular strain, presence of appropriate substrate, temperature, humidity, and available nutrients. There are several hepatotoxic mycotoxins of veterinary significance.

Hepatotoxic Chemicals:

Hepatotoxic Therapeutic Drugs: There are a variety of drugs that have a proven therapeutic application but can cause significant acute or chronic hepatic injury in some animals. A partial list of hepatotoxic therapeutic drugs in dogs and cats is presented in Web Table 8-2. Clearly, these drugs would not be used if the proportion of injured animals was high, but it is important to keep in mind that many drugs have the potential to cause hepatic injury in some patients. The mechanisms by which these drugs cause injury vary by species and by individual. Some therapeutic drugs are predictable toxins, and all members of a particular species are susceptible to liver injury if a sufficient dose is given. But because the therapeutic effect occurs at a lower dose than the toxic dose, liver injury occurs only when overdoses are ingested. Hepatic metabolism (bioactivation) of these compounds is likely to be involved because the site of liver injury is typically centrilobular. Cats are more susceptible than dogs to intoxication by many chemicals because they are relatively deficient in hepatic glucuronyltransferase activity. This phase II enzyme forms conjugates between bioactivated (phase I) xenobiotics and glutathione. When phase II metabolism is overwhelmed, injurious bioactivated products cause liver injury. Cats are more sensitive to acetaminophen intoxication than dogs because of this relative enzyme deficiency. Other therapeutic drugs are idiosyncratic toxins, and they affect only a small minority of patients. The mechanism of injury is not known but may be a consequence of inherited differences in hepatic enzyme content and activity, atypical immune reactions to drug metabolites, or novel antigens created when drug metabolites bind to cellular proteins. For example, the antiinflammatory drug carprofen can occasionally cause acute hepatic necrosis in a variety of dogs, but certain breeds of dogs, such as Labrador retrievers, may be affected more often than others. The tranquilizer diazepam can cause acute fatal hepatic injury in some cats, but the majority of treated cats are unaffected, and dogs do not seem to be adversely affected.

Chronic liver toxicity has been described in dogs receiving any of the anticonvulsants, primidone, phenytoin, and phenobarbital for prolonged periods. The mechanism of hepatotoxicity is unknown. Only a small proportion of dogs receiving these drugs are affected, and these dogs frequently have signs of hepatic failure. The liver is small and has widespread hepatic fibrosis and nodular regeneration (end-stage liver).

Hepatocellular Adenoma: Hepatocellular adenomas are benign neoplasms of hepatocytes. Hepatocellular adenomas have been described most commonly in young ruminants, although hepatic adenomas are likely under-diagnosed in older dogs where they may be diagnosed as well-differentiated hepatocellular carcinomas. The neoplasms usually are single, unencapsulated, variably sized, and red or brown masses that compress adjacent parenchyma. They are typically spherical but may be pedunculated (Fig. 8-61). They are composed of well-differentiated hepatocytes, which form uniform plates that may be two to three cells thick. Hepatic plates in adenomas tend to abut normal adjacent hepatocytes at right angles. Portal tracts and central veins are scarce within the neoplasm, if they can be found at all. Diagnostic criteria to distinguish hepatocellular adenomas from hepatocellular nodular hyperplasia can be somewhat subjective because both arise in livers with no background abnormality, unlike regenerative nodules that arise in damaged livers. Histologically, adenomas are characterized by only one or very few portal tracts, whereas hyperplastic nodules retain normal lobular architecture elements, although the portal tracts are more separated than normal. In other cases, it may be difficult to distinguish hepatocellular adenomas from well-differentiated hepatocellular carcinomas.

Hepatocellular Carcinoma: Hepatocellular carcinomas are malignant neoplasms of hepatocytes. They are uncommon in all domestic species but may occur more frequently in ruminants, particularly sheep. These neoplasms are often solitary, frequently involve an entire lobe, and are well demarcated. They typically consist of friable, gray-white or yellow-brown tissue, which is subdivided into lobules by multiple fibrous bands (Fig. 8-62, A). Malignant hepatocytes characteristically form irregular plates (trabeculae) three or more cells thick, and vascular spaces are present between the trabeculae (Fig. 8-62, B). Crude acini forming a pseudoglandular pattern of neoplastic cells are sometimes present. Within an individual tumor, trabecular, pseudoglandular, and solid patterns may be found. Cells present in the neoplasm range from well-differentiated hepatocytes to atypical or bizarre forms. In the absence of metastasis, which is obviously indicative of malignancy, distinction of well-differentiated carcinoma from adenoma can be difficult, although invasion by malignant hepatocytes at the margin of the adjacent compressed normal hepatocytes and hepatocellular atypia are useful indicators of malignancy. Metastasis to a variety of sites may occur, particularly to lymph nodes within the cranial abdomen, lungs, and seeding into the tissue of the peritoneal cavity. Some hepatocellular carcinomas extensively spread within the liver (intrahepatic metastasis).

Cholangiocellular (Bile Duct) Adenoma: Adenomas of the biliary ducts are uncommon in most species but may be the most common primary hepatic neoplasm in cats. They are usually discrete, firm, and gray or white masses consisting of well-differentiated biliary epithelium. Cholangiomas are glandlike structures formed by tubules lined with cuboidal epithelium and moderate amounts of stroma. The tubules may have narrow lumens or may be distended by fluid-forming cystic structures of variable sizes. Cystic variants, termed biliary cystadenomas, typically have a nonencapsulated, multilocular cystic structure. Hepatocytes are usually compressed at the margins or may on occasion be entrapped by expanding cysts. The stroma of the cyst wall consists of fibrovascular tissue with moderate amounts of collagen. Cysts are lined with benign biliary epithelium (simple cuboidal to flattened). The lining epithelium tends to be more flattened in the biliary cystadenomas, presumably because of compression. Biliary epithelial cells may form papillary projections extending into the cystic spaces.

In cats, large cystic cavities that are lined with flattened biliary epithelium are regarded as adenomas or cystadenomas by some investigators, but it may be more appropriate to consider them to be congenital malformations. Congenital biliary cysts are multiloculated and can involve extensive areas of the liver. Typically, they have flattened epithelium and varying amounts of fibrous tissue, and islands of hepatocytes are often scattered between the cysts.

Cholangiocellular (Bile Duct) Carcinoma: Cholangiocellular carcinomas are malignant neoplasms of biliary epithelium, which usually arise from the intrahepatic ducts, but extrahepatic bile ducts can be affected. These neoplasms occur in all species. A large single mass or multiple nodules may be present within the liver; these typically are firm, raised, often with a central depression (umbilicated), pale gray to tan, and unencapsulated (Fig. 8-63, A). The tumors are composed of cells that retain a resemblance to biliary epithelium. Characteristically, well-differentiated carcinomas are organized into a tubular or acinar arrangement. In less differentiated neoplasms, some acinar arrangements can be detected among solid masses of neoplastic cells. Poorly differentiated carcinomas are composed of packets, islands, or cords, and areas of squamous differentiation can occur. The epithelial components of the neoplasms are usually separated by fibrous connective tissue (Fig. 8-63, B). The amount of connective tissue varies among tumors, but an abundant deposition of collagen, termed a scirrhous response, is relatively common and is responsible for the firm texture of these neoplasms. The margins of cholangiocarcinomas are characterized by multiple sites of local invasion by tumor cells of surrounding hepatic parenchyma. Multiple sites of hepatic necrosis are also common in the adjacent parenchyma.

Metastasis to extrahepatic sites is common, particularly to the adjacent lymph nodes of the cranial abdomen, lungs, or by seeding into the abdominal cavity. Metastasis into the peritoneal cavity can produce variably sized nodules within the mesentery and on the serosal surface of the abdominal viscera.

A unique cutaneous paraneoplastic syndrome can be observed in cats with pancreatic adenocarcinoma or cholangiocarcinoma. This manifests grossly as symmetric alopecia of the ventral trunk and limbs with a glistening appearance. Histologically, affected areas have marked follicular and adnexal atrophy and loss of the stratum corneum of the epidermis.

Cystic Mucinous Hyperplasia of the Gallbladder

Cystic mucinous hyperplasia of the gallbladder mucosa has only been reported in dogs and sheep. There are no apparent abnormalities evident from the exterior of the gallbladder, and the features of cystic hyperplasia can only be appreciated by opening the gallbladder and draining residual bile that may obscure the mucosa. When the bile is rinsed away, affected mucosa is gray-white and has a diffusely thickened, spongelike consistency. Sessile or polypoid masses or large cysts are occasionally found, and they are evident as papillary projections into the lumen of the gallbladder (Fig. 8-79). Numerous 1- to 3-mm cysts within the hyperplastic mucosa impart the characteristic appearance. Histologically, the hallmark of cystic hyperplasia of the gallbladder is the abundance of variably sized cystic spaces that distort and thicken the entire mucosa of the gallbladder. Most of the cysts contain a copious amount of mucus. The majority of the lining epithelial cells are typical of the normal gallbladder epithelium (i.e., tall columnar with abundant apical cytoplasmic mucus). The entire mucosa may be affected. These lesions are usually of no significance to the host. In all likelihood, cystic hyperplasia of the gallbladder frequently goes undetected visually. The cause is not known.

Adenoma

Adenomas of the gallbladder are rare neoplasms but are most common in young cattle and have also been described in dogs, cats, and sheep. They are multinodular or papillary masses that protrude from the mucosal surface and consist of a loose connective tissue stalk that is lined with well-differentiated biliary epithelium (Fig. 8-80).

Carcinoma

Malignant neoplasms of the gallbladder epithelium are rare in domestic animals but have been described in dogs, cats, and cattle. They typically are composed of mucin-secreting epithelial cells and often have a papillary arrangement. Carcinoma of the gallbladder may invade the liver by direct extension and may metastasize to the hepatic lymph nodes and to more distant sites.

Exocrine Pancreatic Atrophy (Juvenile Pancreatic Atrophy)

A distinct syndrome characterized by a dramatically diminished exocrine pancreas has been recognized in several breeds of dog. It is particularly common in the German shepherd dog and rough-coated collies, in which it appears to be inherited as an autosomal recessive trait. In German shepherd dogs, decreased expression of the gene gp25L is observed within the affected pancreas. This lesion is most likely one of atrophy rather than hypoplasia, given recent evidence that suggests that an autoimmune pancreatitis precedes the loss of normal pancreatic parenchyma. The pancreas in affected dogs is small (Fig. 8-81), but islands of normal exocrine pancreatic tissue usually remain. Histologically, there is marked depletion of exocrine pancreatic acinar cells with relative uninvolvement of endocrine islet cells. Young animals are affected, usually between 6 to 12 months of age. Affected dogs have signs typical of maldigestion secondary to exocrine pancreatic insufficiency and rapidly lose weight despite a voracious appetite.

There may be several conditions in which the pancreas is found to be smaller than expected, and the pathogenesis of the lesions may vary, depending on the species. A syndrome termed hypoplasia of the exocrine pancreas occurs sporadically in calves and is characterized by signs of exocrine pancreatic insufficiency. The distinction between atrophy and hypoplasia can be difficult to determine because both processes lead to an abnormally small organ with diminished function. Cells of the hypoplastic exocrine pancreas do not usually contain lipofuscin, which can be seen in atrophic cells.

A recent entity of juvenile pancreatic atrophy has been reported in Greyhounds, in which atrophy of both the exocrine and endocrine pancreas is observed.

Anomalies of the Duct System

The arrangement of the major pancreatic duct or ducts varies between and within species, so a variety of normal arrangements occur. Sheep, for example, have only one pancreatic duct that drains into the common bile duct, whereas cattle and horses typically have two ducts, and several distinct arrangements of the pancreatic ducts have been described in dogs. The pancreatic duct of cats enters the duodenum immediately adjacent to or confluent with the common bile duct. Specific anomalies include congenital stenosis of the pancreatic ducts and cystic dilation of the ducts. Congenital cysts within the pancreas occasionally occur in lambs. Congenital ductal cysts within the pancreas can also be observed in animals with polycystic kidney and/or liver disease.

Ectopic Pancreatic Tissue

Nodules of ectopic pancreatic tissue sometimes are present in the duodenum or other sections of the small bowel, stomach, spleen, gallbladder, and mesentery of the dog and cat. This type of anomaly, normal tissue in an abnormal location, is termed a choristoma.

Pacinian Corpuscles

Pacinian corpuscles are normally present within the interlobular connective tissue of the pancreas and mesentery of the cat, and appear as discrete 1- to 3-mm nodules (Fig. 8-82 and Web Fig. 7-23). The corpuscles should not be mistaken for abnormal structures.

Autolysis

Autolysis of the pancreas is very rapid after death, particularly if the pancreas is traumatized. Postmortem release and activation of pancreatic proteolytic enzymes within the pancreas can hasten tissue breakdown. Thus autolysis may be advanced in the pancreas before it is evident in other organs. As autolysis progresses, the color of the gland may change from its normal pink to dark red or green. The metabolic activity of intestinal bacteria, which can easily gain access to the pancreas, can contribute to the discoloration of the pancreas through hemolysis and tissue decomposition.

Pancreatic Calculi

The formation of concretions or “stones” within the pancreatic duct system is termed pancreolithiasis, and occurs uncommonly in cattle. It is usually an incidental finding at slaughter, and apparently is slightly more common in cattle older than 4 years of age than in younger animals.

Stromal Fat Cell Infiltration

Fat cell infiltration of the interstitial connective tissue of the pancreas occurs occasionally, especially in obese cats. The pancreas itself is usually unaffected, so exocrine pancreatic function is normal, but the dispersion of the parenchyma creates the impression that the pancreas has been replaced by adipose tissue.

Pathogenesis

The three major proposed mechanisms of pancreatitis are as follows:

Obstruction of ductal flow by calculi or parasites can lead to interstitial edema that compresses small-caliber vessels and compromises local blood flow, leading to ischemic damage to acinar cells. Direct damage to acinar cells can be caused by a few specific agents in animals, including compounds found in Cassia occidentalis and T-2 toxin, a trichothecene mycotoxin that affects pigs, and zinc toxicosis of dogs, veal calves, and sheep. Certain therapeutic drugs, such as sulfonamides and potassium bromide–phenobarbital combinations, can damage the pancreas in dogs, and other species are probably similarly affected. Ischemia to the pancreas from a variety of causes may also produce direct injury to the acinar cells. A third mechanism involves aberrant transport of proenzymes within the acinar cells, leading to inappropriate activation of the enzymes within the cells. The association between corticosteroid administration in dogs and an increased risk of acute pancreatitis could possibly be explained by this mechanism. However, many cases of acute pancreatitis commonly occur after dogs have consumed a meal high in fat or some other dietary indiscretion, and the specific mechanism triggering the disease remains unclear. Pancreatitis is occasionally initiated by trauma, usually in dogs and cats as a consequence of some accidental crushing or impact trauma to the abdomen or surgical trauma. Acute pancreatitis in dogs occurs as a consequence of release of activated pancreatic enzymes into the pancreatic parenchyma and adjacent tissue producing autodigestion. Trypsin is believed to be a key player in pancreatitis. Once activated, trypsin in turn can activate proelastase and prophospholipase into elastase and phospholipase A. These enzymes digest pancreatic tissue and adjacent fat and damage blood vessels. Trypsin also activates prekallikrein, leading to involvement of the kinin system, complement, and clotting cascades in affected tissue. These in turn amplify the process, promote thrombosis and hemorrhage, and attract inflammatory cells.

Acute Pancreatitis

The gross lesions of acute pancreatitis are referable to proteolytic degradation of pancreatic parenchyma, vascular damage and hemorrhage, and necrosis of peripancreatic fat by lipolytic enzymes of the pancreas. Mild cases of pancreatitis are characterized by edema of the interstitial tissue of the pancreas. Acute hemorrhagic pancreatitis is more severe, and characteristically, the pancreas is edematous and contains areas that are gray-white, the result of coagulation necrosis, and other areas that are dark red or blue-black, which are hemorrhagic (Fig. 8-83, A). Areas of fat necrosis are manifest as chalky-white foci as a result of saponification of necrotic adipose tissue in the mesentery adjacent to the pancreas. Portions of normal pancreatic parenchyma may be interspersed between affected portions. The peritoneal cavity frequently contains blood-stained fluid, which may contain droplets of fat in the early stage. Peritonitis is manifest by fibrinous adhesions between the affected portions of the pancreas and adjacent tissues.

The microscopic appearance of acute hemorrhagic pancreatitis reflects the gross lesions just described. Characteristic lesions include focally extensive areas of hemorrhage, influx of leukocytes, and coagulation necrosis of the pancreatic parenchyma; accumulation of fibrinous exudate in the interlobular septa; and necrosis and inflammation of fat in the mesentery adjacent to the affected portions of pancreas (Fig. 8-83, B).

Species differences in acute pancreatitis are recognized. For example, in cats, there appear to be two distinct syndromes of acute pancreatitis, one characterized by an acute pancreatic necrosis and a distinct suppurative pancreatitis that is most likely the consequence of ascending bacterial infection.

Acute pancreatitis is usually characterized by vomiting, diarrhea, anorexia, and abdominal tenderness. Acute, severe pancreatitis also produces systemic effects secondary to the release of inflammatory mediators and activated enzymes from the damaged pancreas; these effects include widespread vascular injury and subsequent hemorrhage, shock, and DIC. The liver also is affected in many cases of pancreatitis, as indicated by increased concentrations of serum hepatic enzymes (such as alanine aminotransferase), and sometimes, focal hepatic necrosis.

Acute pancreatitis sufficient to cause clinical disease apparently is considerably less common in species other than the dog and cat. Acute pancreatic necrosis and pancreatitis have been described in the horse, but the pathogenesis of pancreatitis in this species differs from that in the dog and cat. Necrosis and inflammation are the result of migration of strongyle larvae through the pancreas, which results in the release of pancreatic enzymes and enzymatic digestion of the pancreas and surrounding tissue.

Chronic Pancreatitis

Chronic pancreatitis is typically accompanied by fibrosis and parenchymal atrophy. It can occur in all species as a consequence of obstruction of the pancreatic ducts and presumably all of the other mechanisms associated with acute pancreatitis. In the dog, pancreatic fibrosis and chronic pancreatitis are the result of progressive destruction of the pancreas by repeated mild episodes of acute pancreatic necrosis and pancreatitis. An increased incidence of chronic pancreatitis has been reported in cocker spaniels, cavalier King Charles spaniels, collies, and boxer dogs. The pancreas has modest regenerative capacity and responds to injury with replacement fibrosis and atrophy of persisting parenchyma. Thus ongoing destruction of pancreatic tissue causes progressive loss of glandular tissue without replacement (Fig. 8-84). Grossly, the pancreas in affected animals is a distorted, shrunken, nodular mass with fibrous adhesions to adjacent tissue. If a significant portion of the pancreas is affected, dogs may develop signs of exocrine pancreatic insufficiency, with or without signs of endocrine pancreatic insufficiency (diabetes mellitus). However, destruction of pancreatic tissue frequently is not of sufficient magnitude to cause exocrine pancreatic insufficiency, and pancreatic fibrosis is sometimes found as incidental lesions at necropsy of dogs with apparently normal digestive function. In cats, chronic pancreatitis most always manifests as extensive fibrosis, with little inflammation. Fibrosis of the exocrine pancreas also occurs after the necrosis of exocrine pancreatic cells from zinc toxicosis in sheep. Ectasia of the pancreatic ducts with cyst formation also is relatively common in cats with interstitial pancreatic fibrosis.

Chronic pancreatitis and replacement fibrosis occurs sporadically in the horse, usually as a consequence of either parasitic migration or from ascending bacterial infection of the pancreatic ducts. In addition, pancreatitis may occur in horses with chronic eosinophilic gastroenteritis. However, chronic pancreatitis usually is not clinically apparent in the horse, as signs of exocrine pancreatic insufficiency rarely, if ever, occur in this species. Chronic inflammation of the pancreas, characterized by lymphoplasmacytic infiltrates, is most common and important in the dog, but does occur in the cat, horse, and cattle, in which it is rarely of clinical significance.

Pancreatic Nodular Hyperplasia

Nodular hyperplasia of the exocrine pancreas occurs in dogs, cats, and cattle. It is especially common in older dogs and cats. The lesion is of no clinical significance, but it must be distinguished from neoplasms of the endocrine and exocrine pancreas.

These hyperplastic nodules typically are multiple, raised, smooth, and a uniform gray or white on cut surface (Fig. 8-85, A). The nodules may be firmer than the adjacent normal pancreas. Microscopically, these nodules consist of unencapsulated aggregates of acinar cells that may lack zymogen granules or contain an abundance of them (Fig. 8-85, B). Some nodules contain a mixture of the two types of acinar cells. The distinction between hyperplasia and adenoma of the exocrine pancreas is poorly defined in domestic animals.

Pancreatic Adenoma

Adenomas of the exocrine pancreas are extremely rare but have been described in the cat. Those of acinar cell origin share all the features of hyperplastic nodules but are single and larger than normal pancreatic lobules, whereas hyperplastic nodules are not larger than normal lobules; this distinction clearly is somewhat arbitrary.

Pancreatic Carcinoma

Carcinoma of the ductular epithelium or acinar cells of the exocrine pancreas is uncommon in all species. It is most often reported in the dog and cat. The neoplasms may consist of single or multiple nodules of variable size within the pancreas, each of which consists of gray or yellow tissue. Lesions may consist of a single nodule or affect the organ diffusely. Tumors are typically grayish-white to pale yellow with a firm-to-hard consistency (Fig. 8-86, A). Tumors are often gritty when cut. Areas of hemorrhage, mineralization, or necrosis may be present within the neoplasm. The neoplasm is usually firmer than the adjacent pancreas because of proliferation of fibrous connective tissue. Adhesion of the affected pancreas to adjacent tissue may occur. This neoplasm often invades adjacent tissue and seeds the peritoneal cavity. Peritoneal implants form nodules over the mesentery, omentum, and serosa of the abdominal viscera. Metastasis to the regional lymph nodes (pancreatoduodenal, which is inconstantly present and the right hepatic lymph node) is also common, and some carcinomas metastasize widely.

Microscopic features of carcinomas of the exocrine pancreas range from well-differentiated adenocarcinomas with tubular patterns to undifferentiated carcinomas with solid patterns. The amount of fibrous stroma varies considerably and usually is greatest in poorly differentiated neoplasms (Fig. 8-86, B). Zymogen granules similar to those present in normal acinar cells of the pancreas are often absent within the cytoplasm of the neoplastic cells. Mitotic figures are common.

A unique cutaneous paraneoplastic syndrome can be observed in cats with pancreatic adenocarcinoma or cholangiocarcinoma. This manifests grossly as symmetric alopecia of the ventral trunk and limbs with a glistening appearance. Histologically, affected areas have marked follicular and adnexal atrophy and loss of the stratum corneum of the epidermis.